Clinical Trials

The James Cancer Center Columbus, OH

open for enrollment

Nivolumab and Ipilimumab in Treating Patients with HIV Associated Solid Tumors That are Metastatic or Cannot Be Removed by Surgery

Protocol: AMC-095

Full Title

A Phase I Study of Ipilimumab and Nivolumab in Advanced HIV Associated Tumors with an Expansion Cohort in HIV Associated Solid Tumors

Purpose

This phase I trial studies the side effects and best dose of nivolumab when given with ipilimumab in treating patients with human immunodeficiency virus (HIV) associated solid tumors have spread to other places in the body or cannot be removed by surgery. Monoclonal antibodies, such as ipilimumab and nivolumab, may block tumor growth in different ways by targeting certain cells. Ipilimumab is an antibody that acts against a molecule called cytotoxic T-lymphocyte antigen 4 (CTLA-4). CTLA-4 controls a part of your immune system by shutting it down. Nivolumab is a type of antibody that is specific for human programmed cell death 1 (PD-1), a protein that is responsible for destruction of immune cells. Giving ipilimumab with nivolumab may work better in treating patients with HIV associated solid tumors.

Study Objective

PRIMARY OBJECTIVES:

I. To demonstrate safety and feasibility of ipilimumab and nivolumab at the standard doses of drug in solid tumor participants with human immunodeficiency virus (HIV) infection given the possibility of increased toxicity based on immune activation, co-morbidity, or interference with highly active antiretroviral therapy (HAART) therapy. The purpose for this would be to provide appropriate experience and guidelines, if necessary, to allow patients with HIV infections to participate in ongoing trials. (Dose De-escalation and Dose Expansion Cohorts)

SECONDARY OBJECTIVES:

I. To evaluate the effects of single agent nivolumab, and the combination of ipilimumab and nivolumab, on immune function (HIV viral load in plasma using conventional assay, CD4+ and CD8+ cells). (Dose De-escalation Cohort)

II. To preliminarily assess objective response rates associated with treatment for commonly represented tumors. (Dose Expansion Cohort)

III. To evaluate the effects of single agent nivolumab, and the combination of ipilimumab and nivolumab, on immune function (HIV viral load in plasma using conventional HIV assay, CD4+, and CS8+ cells). (Dose Expansion Cohort)

TERTIARY OBJECTIVES:

I. Understand the immune response to agent in the context of antiretroviral therapy (ART), of altered immune function, and repertoire due to prior HIV infection.

II. To evaluate the effects of single agent nivolumab, and the combination of ipilimumab and nivolumab, on intratumor immune cells by immunohistochemistry (IHC) such as PD1, programmed cell death 1 ligand 1 (PDL-1), and others.

III. To evaluate the effects of single agent nivolumab, and the combination of ipilimumab and nivolumab on circulating cytokine markers by multiplex assay, such as: interleukin (IL)-2, IL-4, IL-6, IL-10, IL-8, interferon gamma-induced protein 10 (IP10), chemokine (C-X-C motif) ligand 13 (CXCL13), interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, soluble IL-2 receptor (sIL2R)-alpha, sCD27, soluble TNF receptor (sTNFR)1, and sTNFR2.

IV. To understand the response of human tumor viruses (human papillomavirus [HPV], Kaposi's sarcoma-associated herpesvirus [KSHV]) to agent.

V. To evaluate the effects of single agent nivolumab, and the combination of ipilimumab and nivolumab on herpesvirus loads (Epstein-Barr virus [EBV], Kaposi's sarcoma-associated herpesvirus [KSHV], cytomegalovirus [CMV]) in plasma.

VI. To evaluate the effects of single agent nivolumab, and the combination of ipilimumab and nivolumab on latent herpesvirus (Epstein–Barr virus [EBV], KSHV, cytomegalovirus [CMV]) in peripheral blood mononuclear cells (PBMC).

VII. To evaluate the effects of single agent nivolumab, and the combination of ipilimumab and nivolumab on herpesvirus specific CD8 and CD4 T cells in PBMC.

VIII. In cases of Kaposi sarcoma, to evaluate the effects of single agent nivolumab, and the combination of ipilimumab and nivolumab on viral transcription in tumor biopsies.

IX. In cases of anal cancer, to evaluate the effects of single agent nivolumab, and the combination of ipilimumab and nivolumab on HPV types in anal swabs, when feasible.

X. Understand the response of HIV to agent.

XI. To evaluate the effects of single agent nivolumab, and the combination of ipilimumab and nivolumab on latent HIV loads in PBMC using outgrowth assay.

XII. To evaluate the effects of single agent nivolumab, and the combination of ipilimumab and nivolumab on HIV reactive T cells.

OUTLINE: This is a dose escalation study of nivolumab.

Patients receive nivolumab intravenously (IV) over 60 minutes on day 1. Patients in dose level 2 also receive ipilimumab IV over 90 minutes on day 1 of every third course of nivolumab, and patients in dose level -2 also receive ipilimumab IV over 90 minutes on day 1 of every sixth course of nivolumab. Courses repeat every 14 days for up to 46 courses of nivolumab (with ipilimumab if receiving dose level 2 or -2) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 16 weeks or 112 days (based on 5 half lives).

Are you eligible?

Inclusion Criteria:

Participants must have histologically confirmed solid tumor malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective; participants with uncontrolled Kaposi sarcoma are permitted (KS must be increasing despite HAART and HIV suppression for greater than or equal to 2 months, or stable KS despite HAART for greater than or equal to 3 months)

HIV-1 infection, as documented by any federally approved, licensed HIV rapid test performed in conjunction with screening (or enzyme linked immunosorbent assay [ELISA], test kit, and confirmed by Western blot or other approved test); alternatively, this documentation may include a record demonstrating that another physician has documented the participant's HIV status based on either: 1) approved diagnostic tests, or 2) the referring physician's written record that HIV infection was documented, with supporting information on the participant’s relevant medical history and/or current management of HIV infection

Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam; scans must have been performed within 4 weeks prior to registration; Note: for participants with Kaposi sarcoma, the following apply: at least five measurable cutaneous KS lesions or any number of lesions with systemic unresectable disease with no previous local radiation, surgical, or intralesional cytotoxic therapy that would prevent response assessment

Prior therapy for metastatic disease permitted; at least 4 weeks must have elapsed since prior chemotherapy or biological therapy, 6 weeks if the regimen included carmustine (BCNU) or mitomycin C; radiotherapy must be completed at least 4 weeks prior to registration

Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

Leukocytes >= 2,000/mm^3

Absolute neutrophil count >= 1,000/mm^3

Platelets >= 75,000/mm^3

Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) =< 3 x ULN for subjects with Gilbert’s disease or with atazanavir- or indinavir-induced unconjugated hyperbilirubinemia without aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation and must have a total bilirubin less than 3.0 mg/dL

Serum lipase and amylase < 1.5 x ULN

AST (serum glutamic oxaloacetic transaminase [SGOT])/ALT (serum glutamate pyruvate transaminase [SGPT]) =< 3 X ULN

Creatinine < 1.5 UNL or creatinine clearance (CrCl) > 50 ml/min

Hemoglobin >= 9 g/dL

Serum albumin >= 2.8 g/dL

HIV plasma HIV-1 ribonucleic acid (RNA) below detected limit obtained by Food and Drug Administration (FDA)-approved assays (limit of detection: 75) within 4 weeks prior to registration

CD4 counts:

For Stratum 1: CD4+ cell count greater than 200 cells/mm^3 obtained within 2 weeks prior to enrollment at any U.S. laboratory that has a clinical laboratory improvement amendments (CLIA) certification or its equivalent

For Stratum 2: CD4 cell count between 100-200 cells/mm^3 obtained within 2 weeks prior to enrollment at any U.S. laboratory that has a clinical laboratory improvement amendments (CLIA) certification or its equivalent

Expansion Cohort: CD4 cell count for this cohort will be specified once Stratum 1 and Stratum 2 have completed enrollment

Participants must be purified protein derivative (PPD) negative; PPD positive participants are permitted if prophylaxis has been completed prior to enrollment

Women of childbearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; WOCBP should use an adequate method to avoid pregnancy for 6 months after the last dose of investigational drug; women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropic [HCG]) within 72 hours prior to the start of nivolumab; women must not be breastfeeding; men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year; men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product; women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic men) do not require contraception; WOCBP receiving nivolumab will be instructed to adhere to contraception for a period of 6 months after the last dose of investigational product; men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she (or the participating partner) should inform the treating physician immediately

Participants MUST receive appropriate care and treatment for HIV infection, including antiretroviral medications when clinically indicated, and should be under the care of a physician experienced in HIV management; participants will be eligible regardless of antiretroviral medication (including no antiretroviral medication) provided there is no intention to initiate therapy or the regimen has been stable for at least 4 weeks with no intention to change the regimen within 12 weeks following enrollment

Participants who have hepatitis C (both reactive anti-hepatitis C virus [HCV] antibody and detectable HCV RNA) and hepatitis B (hepatitis B surface antigen [HBsAg] positive and anti-hepatitis B core [HBc]-total positive), may be enrolled, provided total bilirubin is =< 1.5 x institutional ULN, and AST (SGOT) and ALT (SGPT) must be =< 3 X institutional upper limit of normal, and hepatitis B virus (HBV) deoxyribonucleic acid (DNA) < 100 IU/mL (if hepatitis B positive) within 2 weeks prior to enrollment

Ability to understand and to sign a written informed consent document

Criteria for Solid Tumor Expansion Cohort:

Inclusion and exclusion criteria for this cohort are the same as above, with the following rule for CD4 count based on tolerability in Phase I; if, participants with lymphocyte T CD4 count between 100-200/mm^3 (Stratum 2) are shown to tolerate treatment in the Phase I dose de-escalation portion at the same dose level as those with CD4 counts > 200/mm^3 (Stratum 1), participants in the expansion cohort with CD4 counts >= 100/mm^3 are permitted; otherwise, only participants with CD4 count > 200/mm^3 will be enrolled in this cohort; the expansion is limited to only participants with Kaposi sarcoma, lung cancer, and anal cancer

Exclusion Criteria:

Participants who have received any other investigational agents within the 4 weeks prior to enrollment; concurrent radiation therapy is not permitted, except palliative (limited-field) radiation therapy, if all of the following criteria are met:

Repeat imaging demonstrates no new sites of bone metastases

The lesion being considered for palliative radiation is not a target lesion

Participants with known brain metastases or leptomeningeal metastases must be excluded unless they qualify for enrollment as described below because of poor prognosis and concerns regarding progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; participants with brain metastases are permitted if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 4 weeks or more after treatment is complete and within 4 weeks prior to the first dose of nivolumab administration

History of allergic reactions attributed to compounds of similar chemical or biologic composition to ipilimumab, nivolumab, or other agents used in study, or history of severe hypersensitivity reaction to any monoclonal antibody

Participants should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 2 weeks of study drug administration; these drugs may interfere with the activity of ipilimumab and nivolumab if administered at the time of the first ipilimumab dose; inhaled or topical steroids and adrenal replacement doses =< 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease; participants are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if >= 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted; use of anabolic steroids is permitted

Participants with clinical or radiographic evidence of pancreatitis are excluded

Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

Participants should be excluded if they have had prior treatment with an anti-PD-1, anti-programmed cell death ligand 1 (PD-L1), anti-programmed cell death ligand 2 (PD-L2), anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways; prior immune modulating therapy including vaccines may be eligible; prior immune events must be evaluated and the risk for new events which may represent continued sub clinical disease or a new process at previously damaged site or immune potentiation (e.g. ipilimumab followed by IL2 causing bowel perforation, ipilimumab followed by indoleamine 2,3-dioxygenase [IDO] inhibitor resulting in clinical hypophysitis); please keep in mind that inflammatory events may occur weeks to months following the last dose of ipilimumab and possibly nivolumab; assessment of potential effects of prior therapy should include:

Immune status

Organ damage

Risk of autoimmunity

Immunopotentiation

The subject has not recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) =< grade 1 from toxicity due to all prior therapies except =< grade 2 alopecia, neuropathy, and other non-clinically significant adverse events (AEs)

The subject has a primary brain tumor

Participant has >= grade 2 diarrhea (participants with grade 1 diarrhea are eligible provided stool for ova/parasites and stool cryptosporidium studies are negative)

Opportunistic infection within the last 3 months

Participants with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barré syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn’s, ulcerative colitis, hepatitis; and participants with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded; participants with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; participants with rheumatoid arthritis and other arthropathies, Sjögren’s syndrome and psoriasis controlled with topical medication and participants with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible; participants are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event)

Participants who have had evidence of Clostridium (C.) difficile infection, active or acute diverticulitis, intra-abdominal abscess, intra-abdominal abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis, which are known risk factors for bowel perforation, should be evaluated for the potential need for additional treatment before coming on study